An abnormal number of chromosomes, or aneuploidy, is observed in 70% of hematologic malignancies and 95% of solid tumors. The accumulation of these extra chromosomes is nonrandom in many cancers, with some chromosomes being acquired more frequently than others. For example, there is a significant association between the gain of chromosome 8 and myeloid disorders, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Although this link between aneuploidy and cancer is well-established, the mechanistic details are still poorly understood. A significant barrier to investigating questions related to aneuploidy has been a lack of isogenic cell lines with different karyotypes. Recently, I developed two complementary approaches, using microcell mediated chromosome transfer and mosaic trisomy, that enable a direct comparison of diploid and aneuploid cells that are otherwise genetically identical. I also generated induced pluripotent stem cells (iPS) with different karyotypes. I plan to use these cells to investigate the role of trisomy 8 in AML, as well as to identify small molecules and genes which exhibit ploidy- specific lethality. The successful identification of ploidy-specific drugs would represent a novel therapeutic approach in cancer. Candidate Career Goals: My long-term career objective is to obtain a tenure-track position as a physician-scientist in a pediatric hematology/oncology department. The K08 award will provide the protected time I need for advanced training in order to achieve this career goal. This research proposal is part of a structured plan with scientific, technical, clinical, and career development components. The research will performed under the guidance of Dr. David Pellman in the Division of Pediatric Hematology/Oncology at Children's Hospital Boston/Dana Farber Cancer Institute. The career development plan builds upon my prior research and clinical experiences with the goal of ensuring that I acquire the expertise required to become a successful, independent investigator with a focus on cancer biology and clinical pediatric oncology. Environment: The Dana-Farber Cancer Institute (DFCI), Children's Hospital Boston and Harvard University are internationally recognized research programs with a number of expert researchers in the areas of stem cell biology, hematopoiesis, and cancer cell biology. Furthermore, The Division of Pediatric Hematology/Oncology at Children's Hospital Boston/Dana Farber Cancer Institute has a distinguished record of training successful physician scientists. I have assembled an excellent mentoring and advisory committee, consisting of Dr. David Pellman, Dr. Scott Armstrong, Dr. George Daley and Dr. Nathanael Gray, that will guide my research and training experiences. PUBLIC HEALTH RELEVANCE: Many cancer cells have an abnormal number of chromosomes. This proposal describes an innovative approach to study the effect of extra chromosomes on the development of leukemia. The long-term goals of this project are to determine how cancers arise and to develop new anti- cancer therapies that specifically target cells with extra chromosomes. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" section above summarizes the final opinions of the committee.